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Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns.

Dewey CN, Rogozin IB, Koonin EV - BMC Genomics (2006)

Bottom Line: In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed.Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals.Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information NLM, National Institutes of Health, Bethesda, MD 20894, USA. cdewey@biostat.wisc.edu <cdewey@biostat.wisc.edu>

ABSTRACT

Background: The signals that determine the specificity and efficiency of splicing are multiple and complex, and are not fully understood. Among other factors, the relative contributions of different mechanisms appear to depend on intron size inasmuch as long introns might hinder the activity of the spliceosome through interference with the proper positioning of the intron-exon junctions. Indeed, it has been shown that the information content of splice sites positively correlates with intron length in the nematode, Drosophila, and fungi. We explored the connections between the length of vertebrate introns, the strength of splice sites, exonic splicing signals, and evolution of flanking exons.

Results: A compensatory relationship is shown to exist between different types of signals, namely, the splice sites and the exonic splicing enhancers (ESEs). In the range of relatively short introns (approximately, < 1.5 kilobases in length), the enhancement of the splicing signals for longer introns was manifest in the increased concentration of ESEs. In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed. Conceivably, accumulation of A-rich ESE motifs beyond a certain limit is incompatible with functional constraints operating at the level of protein sequence evolution, which leads to compensation in the form of evolution of the splice sites themselves toward greater strength. In addition, however, a correlation between sequence conservation in the exon ends and intron length, particularly, in synonymous positions, was observed throughout the entire length range of introns. Thus, splicing signals other than the currently defined ESEs, i.e., potential new classes of ESEs, might exist in exon sequences, particularly, those that flank long introns.

Conclusion: Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals. Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

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Rates of synonymous and nonsynonymous codon substitutions in exon ends over different lengths of the flanked intron. Codons split between exons were excluded from the analysis. The frequencies of both synonymous and nonsynonymous codon substitutions in exon ends flanking long introns (>1 kb, the median average mouse/rat intron length) show weak negative correlation (synonymous: R = -0.0546, P = 3.06E-27, nonsynonymous: R = -0.0297, P = 4.24E-9) with intron length. The data is for mouse/rat orthologous intron pairs. Mean standard error bars are given for each substitution rate.
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Figure 6: Rates of synonymous and nonsynonymous codon substitutions in exon ends over different lengths of the flanked intron. Codons split between exons were excluded from the analysis. The frequencies of both synonymous and nonsynonymous codon substitutions in exon ends flanking long introns (>1 kb, the median average mouse/rat intron length) show weak negative correlation (synonymous: R = -0.0546, P = 3.06E-27, nonsynonymous: R = -0.0297, P = 4.24E-9) with intron length. The data is for mouse/rat orthologous intron pairs. Mean standard error bars are given for each substitution rate.

Mentions: If intron length is correlated with splicing signal strength, one would expect that sequences flanking long introns (sequences that might contain additional splicing signals) would be more conserved than those flanking short introns. Indeed, we found that both synonymous and nonsynonymous sites were more conserved in exon ends adjacent to long introns (Figure 6). The effect was notably more significant for the synonymous sites, which is compatible with the hypothesis that stronger sequence conservation in regions adjacent to long exons might be due to the presence of exonic splicing signals.


Compensatory relationship between splice sites and exonic splicing signals depending on the length of vertebrate introns.

Dewey CN, Rogozin IB, Koonin EV - BMC Genomics (2006)

Rates of synonymous and nonsynonymous codon substitutions in exon ends over different lengths of the flanked intron. Codons split between exons were excluded from the analysis. The frequencies of both synonymous and nonsynonymous codon substitutions in exon ends flanking long introns (>1 kb, the median average mouse/rat intron length) show weak negative correlation (synonymous: R = -0.0546, P = 3.06E-27, nonsynonymous: R = -0.0297, P = 4.24E-9) with intron length. The data is for mouse/rat orthologous intron pairs. Mean standard error bars are given for each substitution rate.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1713244&req=5

Figure 6: Rates of synonymous and nonsynonymous codon substitutions in exon ends over different lengths of the flanked intron. Codons split between exons were excluded from the analysis. The frequencies of both synonymous and nonsynonymous codon substitutions in exon ends flanking long introns (>1 kb, the median average mouse/rat intron length) show weak negative correlation (synonymous: R = -0.0546, P = 3.06E-27, nonsynonymous: R = -0.0297, P = 4.24E-9) with intron length. The data is for mouse/rat orthologous intron pairs. Mean standard error bars are given for each substitution rate.
Mentions: If intron length is correlated with splicing signal strength, one would expect that sequences flanking long introns (sequences that might contain additional splicing signals) would be more conserved than those flanking short introns. Indeed, we found that both synonymous and nonsynonymous sites were more conserved in exon ends adjacent to long introns (Figure 6). The effect was notably more significant for the synonymous sites, which is compatible with the hypothesis that stronger sequence conservation in regions adjacent to long exons might be due to the presence of exonic splicing signals.

Bottom Line: In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed.Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals.Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

View Article: PubMed Central - HTML - PubMed

Affiliation: National Center for Biotechnology Information NLM, National Institutes of Health, Bethesda, MD 20894, USA. cdewey@biostat.wisc.edu <cdewey@biostat.wisc.edu>

ABSTRACT

Background: The signals that determine the specificity and efficiency of splicing are multiple and complex, and are not fully understood. Among other factors, the relative contributions of different mechanisms appear to depend on intron size inasmuch as long introns might hinder the activity of the spliceosome through interference with the proper positioning of the intron-exon junctions. Indeed, it has been shown that the information content of splice sites positively correlates with intron length in the nematode, Drosophila, and fungi. We explored the connections between the length of vertebrate introns, the strength of splice sites, exonic splicing signals, and evolution of flanking exons.

Results: A compensatory relationship is shown to exist between different types of signals, namely, the splice sites and the exonic splicing enhancers (ESEs). In the range of relatively short introns (approximately, < 1.5 kilobases in length), the enhancement of the splicing signals for longer introns was manifest in the increased concentration of ESEs. In contrast, for longer introns, this effect was not detectable, and instead, an increase in the strength of the donor and acceptor splice sites was observed. Conceivably, accumulation of A-rich ESE motifs beyond a certain limit is incompatible with functional constraints operating at the level of protein sequence evolution, which leads to compensation in the form of evolution of the splice sites themselves toward greater strength. In addition, however, a correlation between sequence conservation in the exon ends and intron length, particularly, in synonymous positions, was observed throughout the entire length range of introns. Thus, splicing signals other than the currently defined ESEs, i.e., potential new classes of ESEs, might exist in exon sequences, particularly, those that flank long introns.

Conclusion: Several weak but statistically significant correlations were observed between vertebrate intron length, splice site strength, and potential exonic splicing signals. Taken together, these findings attest to a compensatory relationship between splice sites and exonic splicing signals, depending on intron length.

Show MeSH